Multidrug resistance, a phenomenon defined as the ability of cells to acquire resistance to a wide range of structurally and functionally distinct cytotoxic or cytostatic compounds, is often caused by overexpression of drug efflux pumps resulting in the expulsion of a wide variety of molecules, and presents a major obstacle in the treatment of infectious disease caused by bacterial and fungal pathogens. MDR is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by up-regulation of transporters (e.g. P-glycoprotein) that facilitate extrusion of a wide range of toxic chemicals and drugs. The molecular mechanisms, however, are poorly understood.
Pathogenic fungi, especially Candida species, have emerged as important and prevalent opportunistic infections in individuals with compromised immunity, including those suffering from AIDS, cancer patients treated with chemotherapy, transplant recipients on immunosuppressive drugs, and patients with advanced diabetes. Candida species now account for 8% to 9% of all blood stream infections, with crude mortality rates of 40%. Significantly, both intrinsic and acquired MDR is an important complication of fungal infections. C. glabrata, which exhibits strong MDR, is emerging as a clinically important fungal pathogen, accounting, for example, for 20% to 24% of Candida blood stream infections in the U.S. There is thus an urgent need to elucidate the mechanisms underpinning MDR in pathogenic fungi to develop novel antifungal treatments.